Pharmacokinetics of iontophoretic sumatriptan administration

ABSTRACT

Improved pharmacokinetic profiles for the iontophoretic delivery of sumatriptan are described.

BACKGROUND

The process of iontophoresis was described by LeDuc in 1908 and hassince found commercial use in the delivery of ionically chargedtherapeutic agent molecules such as pilocarpine, lidocaine anddexamethasone. In this delivery method, ions are carried into the skinby an electrical current that is supplied by a positive and negativeelectrode. Positive ions are carried away from the positive anode, whilenegative ions are carried away from the negative cathode.

Earlier, and some present, iontophoretic devices have been typicallyconstructed of two electrodes attached by adhesive materials to apatient, each connected by a wire to a remote power supply. A recentpublication has indicated that sumatriptan can be transdermallytransported effectively using iontophoresis (Femenia-Font et al, J.Pharm Sci 94, 2183-2186, 2005). In this study, iontophoretic transportof sumatriptan was found to be at a rate 385 fold higher than passivetransport.

SUMMARY

The invention pertains, at least in part to a method for treating asumatriptan responsive state in a subject. The method includesiontophoretically administering to the subject an amount of asumatriptan using a current of 3.5 mA or greater for at least a portionof the treatment period.

In another embodiment, the invention also pertains to a method fortreating a sumatriptan responsive state in a subject. The methodincludes iontophoretically administering to the subject an amount of aneffective amount of sumatriptan using a current of about 4 mA for a highcurrent treatment period of about one hour and a current of about 2 mAfor a subsequent low current treatment period.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a sumatriptan responsive state in a subject. Themethod includes iontophoretically administering to a subject an amountof sumatriptan resulting in an AUC_(0-inf) 95% confidence intervalbetween about 99 hr*ng/mL and about 128 hr*ng/mL and a C_(max) 95%confidence interval of between about 20 to about 28 ng/mL.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a sumatriptan responsive state in a subject. Themethod includes administering to a subject an amount of sumatriptanresulting in a AUC_(0-inf) (of sumatriptan in the subject's plasma)within a 95% confidence interval between about 99 and about 128hr*ng/mL.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a sumatriptan responsive state in a subject. Themethod includes administering to a subject an amount of sumatriptanresulting in a C_(max) (in said subject's plasma) of between about 20and about 28 ng/mL, or between about 23 and about 25 ng/mL and whereinthe plasma concentrations of sumatriptan are sustained at therapeuticlevels for at least three hours.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a sumatriptan responsive state in a subject. Themethod includes iontophoretically administering to a subject an amountof sumatriptan resulting in an AUC_(0-inf) between about 99 hr*ng/mL andabout 128 hr*ng/mL and a C_(max) between about 20 to about 28 ng/mL.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a sumatriptan responsive state in a subject. Themethod includes administering to a subject an amount of sumatriptanresulting in a AUC_(0-inf) (of sumatriptan in the subject's plasma)between about 99 and about 128 hr*ng/mL.

The invention also pertains, at least in part, to a method for treatinga subject for a sumatriptan responsive state. The method includesadministering to a subject an effective amount of sumatriptan using aniontophoretic patch for an effective treatment period. The patch may usea current density of at least about 0.10 mA/cm² or higher (e.g., about0.30 mA/cm² or higher, or about 0.40 mA/cm²) for at least a portion ofthe treatment period.

The invention also pertains, at least in part, to a method for treatinga subject for a sumatriptan responsive state. The method includesadministering to a subject an effective amount of sumatriptan using aniontophoretic patch for an effective treatment period comprising a highcurrent density period and a low current density period. In a furtherembodiment, the high current density period has a current density ofabout 0.13 mA/cm² or higher (e.g., about 0.4 mA/cm²) and said lowcurrent density period has a current density of about 0.067 mA/cm² orhigher (e.g., about 0.2 mA/cm²). In yet another further embodiment, thehigh current density period has a current density of about 0.1 mA/cm² orhigher (e.g., about 0.3 mA/cm²) and said low current density period hasa current density of about 0.05 mA/cm² or higher (e.g., about 0.15mA/cm²).

In a further embodiment, the invention also pertains, at least in part,to a method for treating a subject for a sumatriptan responsive state.The method includes administering to the subject an effective amount ofsumatriptan, wherein the effective amount of sumatriptan is administeredwithout substantial adverse effects.

In another further embodiment, the invention also features a method oftreating a sumatriptan responsive state in a subject, by transdermallyadministering to a subject an effective amount of sumatriptan, whereinthe administration of sumatriptan results in an AUC_(0-inf) coefficientof variance of less than about 25%.

In yet another further embodiment, the invention also pertains, at leastin part, to a method of treating a sumatriptan responsive state in asubject. The method includes transdermally administering to the subjectan effective amount of sumatriptan, wherein the administration ofsumatriptan results in an AUC_(0-inf) coefficient of variance less thantwice the AUC_(0-inf) coefficient of variance for subcutaneousadministration of sumatriptan for a similar sample size.

DETAILED DESCRIPTION

One advantage of the methods of the present invention over oraladministration of sumatriptan is that there is less variation ofpharmacokinetic parameters with the present invention as compared tooral or nasal delivery. In contrast to oral delivery of sumatriptan, theamount of variance between the subjects after being administeredsumatriptan iontophoretically is a fraction of the amount of variancebetween the subjects after being administered sumatriptan orally.

Another advantage the methods of the present invention is that themethods allow sumatriptan to be administered such that the AUC_(0-inf)is similar to that of other dosage forms such as systemic, oral or nasaladministration, while the C_(max) is substantially reduced. By doingthis, the amount of sumatriptan delivered systemically may be similar tothe other methods, but concentration spiking is preferably reduced.Another advantage of the methods of the present invention is that theconcentration of sumatriptan in the subject generally reachestherapeutic levels less than an hour after administration begins.Furthermore, therapeutic levels of sumatriptan may be maintained for adesired length of time, e.g., four to five hours.

The methods of the invention can be described, at least in part, by theuse of pharmacokinetic parameters. Pharmacokinetic parameters may becalculated using methods known in the art. In the examples describedherein, the pharmacokinetic parameters were calculated using anon-compartmental method, with the aid of the WinNonlin™ computerprogram (WinNonlin Professional, Version 5.2, Pharsight Corp, Palo Alto,Calif.). The parameters calculated include:

-   AUC_(0-last) Area under the concentration versus time curve from    time 0 to the last time point with measurable concentration (C_(t));    calculated using linear trapezoid rule.-   AUC_(0-inf) Area under the concentration versus time curve from time    0 to infinity; calculated as AUC_(0-last)+C_(t)/λ_(z2).-   C_(max) Maximum observed drug concentration.-   T_(max) Time of maximum drug concentration.-   Cl/F Apparent total body clearance; calculated as Dose/AUC_(inf) and    where F was assumed to be 1.0 after SQ injection-   λ_(z) The terminal elimination phase rate constant; calculated using    non-linear regression analysis-   t_(1/2) Terminal elimination half-life; calculated as 0.693/λ₂.

In one embodiment, the invention pertains, at least in part to a methodfor treating a sumatriptan responsive state in a subject. The methodincludes iontophoretically administering to the subject an amount of asumatriptan using a current of 3.5 mA or greater for at least a portionof the treatment period.

The term “sumatriptan responsive states” includes migraines, familiarhemiplegic migraines (with and without aura), chronic paroxysmalheadaches, cluster headaches, migraine headaches, basilar migraines, andatypical headaches accompanied by autonomic symptoms, such as cyclicvomiting syndrome.

The term “treat” includes the reduction or amelioration of one or moresymptoms of a sumatriptan responsive state. It also may include theprevention of the occurrence or reoccurrence of the sumatriptanresponsive state.

The term “effective amount” includes the amount of sumatriptan which iseffective to treat a particular sumatriptan responsive state.

The term “subject” includes living organisms capable of havingsumatriptan responsive states (e.g., mammals). Examples of subjectsinclude humans, dogs, cats, horses, cows, goats, rats and mice. In oneembodiment, the subject is a human. In a further embodiment, the termincludes subjects suffering from a sumatriptan responsive state.

The term “iontophoretically” or “iontophoretic” includes methods ofadministration which use electric current to promote the absorption of atherapeutic compound (e.g., sumatriptan) from the iontophoretic device(e.g., patch) through the skin of a subject.

The term “iontophoretic patch” or “iontophoretic transdermal patch”includes devices which allow for the iontophoretic administration ofsumatriptan through the skin of a subject. In one embodiment, the patchcomprises electrical components, sumatriptan, and an adhesive backinglayer. In a further embodiment, the iontophoretic patch may be anintegrated device, e.g., a wearable, self contained devices which doesnot require a separate controller or power source. In another furtherembodiment, the iontophoretic patch of the invention is not integrated,e.g., requires a separate controller, power source, etc, and may notnecessarily be wearable.

In a further embodiment, the methods of the invention use a current ofabout 3.6 mA or greater, about 3.7 mA or greater, about 3.8 mA orgreater, about 3.9 mA or greater, about 4.0 mA or greater, about 4.1 mAor greater, about 4.2 mA or greater, or greater than about 4.5 mA toadminister the sumatriptan.

Advantageously, the methods of the invention use a current of about 4.0mA for at least a portion of the treatment period (“high currenttreatment period”). In a further embodiment, the high current treatmentperiod is between about thirty minutes to about two hours, between aboutthirty minutes and ninety minutes, or about one hour.

In a further embodiment, the methods of the invention may also furthercomprise a low current treatment period (preferably, subsequent to thehigh current treatment period). The low current treatment period mayemploy a current of between about 1.5 to about 2.5 mA (e.g., about 2mA). In another further embodiment, the low current treatment period isbetween about 2 hours to about 6 hours, between about 2 hours and about5 hours, between about 2 hours and about 4 hours, or about three hoursin length.

In a further embodiment, the invention also pertains, at least in partto a method for treating a sumatriptan responsive state in a subject, byiontophoretically administering to a subject an amount of sumatriptanusing current of about 4 mA for a high current treatment period of aboutone hour and a current of about 2 mA for a subsequent low currenttreatment period. In a further embodiment, the sumaptriptan isiontophoretically administered using a iontophoretic patch.

In a further embodiment, the invention pertains, at least in part, to amethod for treating a sumatriptan responsive state in a subject. Themethod includes administering to a subject an amount of sumatriptan,such that the sumatriptan responsive state is treated. In thisembodiment, the amount of sumatriptan results in an AUC_(0-inf) ofbetween about 99 hr*ng/mL and about 128 hr*ng/mL (e.g., between about107 hr*ng/mL and about 115 hr*ng/mL, or about 112 hr*ng/mL and about 114hr*ng/mL) and a C_(max) of between about 20 to about 28 ng/mL (e.g.,preferably about 22.5 ng/mL and about 25 ng/mL).

In a further embodiment, the invention also pertains to a method fortreating a sumatriptan responsive state in a subject. The methodincludes iontophoretically administering to a subject an amount ofsumatriptan, resulting in an AUC_(0-inf) (for sumatriptan) with a 95%confidence interval between about 99 and about 128 hr*ng/mL.

The term “confidence interval” refers, generally, to a given proportion(here 95%) which reflects the chance that a random sampling would bewithin these values.

In a further embodiment, the invention also pertains to another methodfor treating a sumatriptan responsive state in a subject. The methodincludes iontophoretically administering to a subject an amount ofsumatriptan, resulting in an C_(max) with a 95% confidence intervalbetween about 20 and about 28 ng/mL.

In a further embodiment, the invention also pertains to yet anothermethod for treating a sumatriptan responsive state in a subject. Themethod includes iontophoretically administering to a subject an amountof sumatriptan, resulting in an C_(max) (in said subject's plasma forsumatriptan) of between about 20 to about 28 ng/mL, or between about 23to about 25 ng/mL and wherein the plasma concentration of sumatriptanare sustained at therapeutic levels for at least three hours.

In a further embodiment, the term “sustained” includes levels (e.g.,plasma levels of sumatriptan) which fluctuate less than about 20%, lessthan about 10%, or less than about 5% over a period (e.g., the lowcurrent period).

In another embodiment, therapeutic plasma level of sumatriptan occurless than one hour after the beginning of sumatriptan treatment. Theterm therapeutic plasma levels include levels of sumatriptan which arecapable of treating a subject's symptoms for the sumatriptan responsestate. Examples of therapeutic levels include concentrations of betweenabout 10-28 ng/mL of sumatriptan in the subject's plasma. In otherembodiment, the therapeutic levels are between about 20-28 ng/mL.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a sumatriptan responsive state in a subject. Themethod includes iontophoretically administering to a subject an amountof sumatriptan resulting in an AUC_(0-inf) between about 99 hr*ng/mL andabout 128 hr*ng/mL and a C_(max) between about 20 to about 28 ng/mL.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a sumatriptan responsive state in a subject. Themethod includes administering to a subject an amount of sumatriptanresulting in a AUC_(0-inf) (of sumatriptan in the subject's plasma)between about 99 and about 128 hr*ng/mL.

In another further embodiment, the iontophoretic patch of the inventionemploys a current of at least about 3.5 mA (e.g., about 4 mA) forbetween about thirty minutes and ninety minutes (e.g., for about anhour) for a high current treatment period. The high current treatmentperiod may further be followed by a low current treatment period. Thelow current treatment period may use a current of between about 1.5 mAto about 2.5 mA (e.g., about 2 mA) for between about two to about sixhours (e.g., about three hours).

In another embodiment, the invention also pertains, at least in part, toa method for treating a subject for a sumatriptan responsive state. Themethod includes administering to the subject an effective amount ofsumatriptan, wherein the effective amount of sumatriptan is administeredwithout substantial adverse effects.

The term “substantial adverse effects” includes those listed on currenttriptan product labels. Examples of these substantial adverse effectsinclude atypical sensations (e.g., sensation of warmth or cold,parethesias, etc.) and pain and pressure sensations. Examples of adverseeffects include, but are not limited to, mucosal burning sensations, eardiscomfort, facial pain, feeling hot, flushing, head discomfort, hotflush, paraesthesia, sense of heaviness, sensation of pressure, neckpain, etc.

In a further embodiment, the term “substantial adverse effects” do notinclude skin irritation or “application site disorders” caused by thepatch itself.

The term “transdermal” include methods of administration of sumatriptanthrough the skin of a subject without substantially puncturing the skin.Examples of transdermal delivery methods include absorption,electroporation, radio frequency (RF) poration and iontophoresis.

In a further embodiment, the methods of the invention include a methodof treating a sumatriptan responsive state in a subject, bytransdermally administering to the subject an effective amount ofsumatriptan, such that the administration of sumatriptan results in anAUC_(0-inf) coefficient of variance of less than about 25%. In a furtherembodiment, the coefficient of variance is less than about 20% (for agroup of subjects when administered the same dosage of sumatriptan usingthe same method and treatment profile).

The coefficient of variance can be measured is a measure of thevariation of a set of data points. It is calculated by dividing thestandard deviation by the mean.

In another further embodiment, the invention features a method oftreating a sumatriptan responsive state in a subject, by transdermallyadministering to the subject an effective amount of sumatriptan, suchthat the sumatriptan responsive state is treated. In this method, theadministration of sumatriptan results in an AUC_(0-inf) coefficient ofvariance less than twice the AUC_(0-inf) coefficient of variance forsubcutaneous administration of sumatriptan for a similar sample size(e.g., the AUC_(0-inf) CV for the sumatriptan administered to subjectsusing iontophoresis will be less than twice the AUC_(0-inf) CV for asimilarly sized group of subjects administered sumatriptansubcutaneously).

In an embodiment, the invention pertains, at least in part, to aniontophoretic transdermal patch for the delivery of sumatriptan or asalt thereof. The patch comprises an anode reservoir, a cathodereservoir and appropriate electrical circuitry for performing themethods of the invention.

The invention pertains, at least in part, to a method for treating asubject for a sumatriptan responsive state. The method includesadministering to a subject an effective amount of sumatriptan using aniontophoretic patch for an effective treatment period. The patch may usea current density of at least about 0.10 mA/cm² or higher, 0.2 mA/cm² orhigher, 0.30 mA/cm² or higher, or about 0.4 mA/cm² or higher for atleast a portion of the treatment period.

In one embodiment, the effective amount is effective to treat amigraine. In this case, the effective amount of sumatriptan may be aconcentration of about 10 ng/mL or greater, about 11 ng/mL or greater,about 12 ng/mL or greater, about 13 ng/mL or greater, about 14 ng/mL orgreater, about 15 ng/mL or greater, about 16 ng/mL or greater, about 17ng/mL or greater, about 18 ng/mL or greater, about 19 ng/mL or greater,about 20 ng/mL or greater, about 21 ng/mL or greater, about 22 ng/mL orgreater, or about 22.5 ng/mL or greater in said subject's blood orplasma. In another embodiment, the effective amount of sumatriptan isgreater than about 5 mg, greater than about 10 mg, or greater than about15 mg. In one further embodiment, the effective amount of sumatriptan isabout 10 to about 25 ng/mL in said subject's plasma.

In certain embodiments, the patch has an iontophoretically activesurface area of about 10 cm² or greater, 15 cm² or greater, 17.5 cm² orgreater, 20 cm² or greater, 22.5 cm² or greater, 25 cm² or greater, 27.5cm² or greater or 30 cm² or greater.

Preferably, the high current density period precedes the low currentdensity period. Furthermore, preferably, the current density of theseperiods are different and the current density of the high currentdensity period is at least 10%, at least 30%, at least 40%, at least50%, or at least 100% greater than the current density of the lowcurrent density period.

In a further embodiment, the treatment period comprises two portions,e.g., a high current density period and a lower current density period.Preferably, the higher current density period precedes the lower currentdensity period. Although not to be limited by theory, it is believedthat having the higher current density period first may provide relieffor the subject for one or more the symptoms of the sumatriptanresponsive state, e.g., migraine. The lower current density period maythen prevent or delay the reoccurrence of the sumatriptan responsivestate.

In one embodiment, the higher current density period is about 30 minutesto about 90 minutes, e.g., about an hour. The length and intensity ofthe higher current density period may be selected such that the subjectmay be treated for the acute symptoms of the sumatriptan responsivestate. For example, the higher current density period may provide thesubject with an effective dose of sumatriptan such that the primarysymptoms of the sumatriptan responsive state, e.g., migraine, areeliminated or ameliorated.

In another further embodiment, when the iontophoretic pad is about 30cm², the current density of the higher current density period is about0.10 mA/cm² to about 0.18 mA/cm². The higher current densities allowsfor the quick delivery of therapeutically effective amounts ofsumatriptan. Examples of currents which are used for the high currentdensity periods include currents of about 2.5 mA to about 5 mA, e.g.,about 3 mA to about 4 mA. In another further embodiment wherein theiontophoretic pad is about 10 cm², the current densities may be betweenabout 0.25 mA/cm² to about 0.5 mA/cm², or about 0.3 mA/cm² to about 0.4mA/cm².

In another embodiment, the lower current density period is about twohours or longer, three hours or longer, four hours or longer, or fivehours or longer. The lower current density period may be selected suchthat the subject is effectively treated for the sumatriptan responsivestate, e.g., migraine. The lower current density time may be selectedsuch that it is effective to ameliorate the symptoms of the sumatriptanresponsive state or prevent the immediate reoccurrence of thesumatriptan responsive state.

In a further embodiment, the current density of the low current densityperiod for a 30 cm² patch is between about 0.04 mA/cm² and 0.09 mA/cm²,or about 0.05 mA/cm² to about 0.08 mA/cm². Preferably, the low currentdensity period is selected such that it treats the subject for thesumatriptan responsive state. In one embodiment, the low current densityperiod is about 2 hours or longer, about 2.5 hours or longer, about 3hours or longer, about 3.5 hours or longer, about 4 hours or longer,about 4.5 hours or longer, about 5 hours or longer, about 5.5 hours orlonger, or about 6 hours or longer. In another further embodiment, thelow current density period is about 2.5 to about 6 hours long. In afurther embodiment, the current density of the low current densityperiod for a 10 cm² patch is between about 0.125 mA/cm² and 0.25 mA/cm²,or about 0.15 mA/cm² to about 0.2 mA/cm².

In another further embodiment, the low current density period uses acurrent of between about 1.25 mA to about 2.5 mA, or between about 1.5mA to about 2 mA.

Preferably, the patch does not substantially irritate a subject's skinwhen used in accordance with the methods of the invention. The language“does not substantially irritate a subject's skin” includes patcheswhich result in a skin erythema score of 1.50 or less, or 1.00 or lessabout two hours after patch removal. In another further embodiment, thelanguage “does not substantially irritate a subject's skin” includespatches which result in a skin erythema score of 2.00 or less, or 1.00or less immediately after patch removal.

In one embodiment, the invention also pertains to a method for treatinga subject for a sumatriptan responsive state. The method includesadministering to the subject an effective amount of sumatriptan using aniontophoretic patch for an effective treatment period comprising a highcurrent density period and a low current density period.

In another embodiment, the high current density period has a currentdensity of between about 0.1 mA/cm² and about 0.3 mA/cm² and the lowcurrent density period has a current density of between about 0.05mA/cm² and about 0.15 mA/cm². In this embodiment, the high currentdensity period may be about 1 hour and the low current density periodmay be about five hours.

In yet another embodiment, the high current density period has a currentdensity of between about 0.13 mA/cm² and about 0.4 mA/cm² and the lowcurrent density period has a current density of between about 0.067mA/cm² and about 0.2 mA/cm². In this embodiment, the high currentdensity period may be about 1 hour and the low current density periodmay be about three to five hours.

EXEMPLIFICATION OF THE INVENTION Example 1 Use of lontophoretic Patchesto Deliver Sumatriptan Succinate

A single center, open label, single-dose, five period study wasconducted to compare the pharmacokinetics of four prototypes ofsumatriptan iontophoretic transdermal patches of the invention with 100mg oral sumatriptan succinate in healthy volunteers. Subjects, atminimum, participated in Treatment A and Treatment B.

The iontophoretic patches used were self-contained, with an externalpower source, designed to be applied to the surface of the skin and todeliver medication systemically.

The patch treatments and prototype iontophoretic patches prepared forthis example, are detailed in the Table 1 below.

TABLE 1 Iontophoretic Patch Dosing Treatments Theoretical Anode WearDelivery mA Electrode Period Treatment Placement Time(hr) Waveform DoseMinutes Size 1 A Upper arm 6 3 mA for 3 mg/hr × 1 hr + 630  5 cm² 1.0 hrthen 1.5 mg/hr × 1.5 mA for 5 hrs = 5.0 hrs 10.5 mg 3 C Upper arm 6 3 mAfor 3 mg/hr × 1 hr + 630  5 cm² 1.0 hr then 1.5 mg/hr × 1.5 mA for 5 hrs= 5.0 hrs 10.5 mg 4 D Upper back 6 4 mA for 4 mg/hr × 1 hr + 840 10 cm²1.0 hr then 2 mg/hr × 2.0 mA for 5 hr = 5.0 hrs 14.0 mg 5 E Upper back 44 mA for 4 mg/hr × 1 hr + 600 10 cm² 1.0 hr then 2 mg/hr × 2.0 mA for 3hr = 3.0 hrs 10.0 mg

Nine subjects participated in Treatment B a 100 mg sumatriptan succinateoral tablet. The study consisted of a Screening Visit followed byTreatments A, B, C, D and E. Each of the treatment periods wereseparated by a 2 day washout period. During the screening period, eachsubject had a physical examination, including vital signs, a hepatitisscreen, HIV screen, urine drug screening, an electrocardiogram,pregnancy test (females only), ethanol breath test and clinicallaboratory tests. In addition, the medical history and demographic dataincluding age and race was recorded. All assessments were conducted nomore than 28 days prior to the first dosing. Subjects who met all of theinclusion criteria and none of the exclusion criteria were admitted onDay-1. During the confinement periods, subjects did not engage instrenuous activity and abstained from alcohol and tobacco. During eachconfinement period, the subjects received study dosing after anovernight fast. The subjects were dosed at 0800 hours on Day 1 of eachdosing period. For periods 1 and 2, the subjects were confined to thestudy center the morning before dosing of Treatment A (Day-1) andthrough the 24 hour post dose assessments for Treatment B.

For periods 3-5, the subjects were confined to the study center themorning before dosing of Treatment C (Day-1) and through the 24 hourpost dose assessments for Treatment E. Each dosing period lastedapproximately 2 days with at least a 2 day washout period betweendosings. Study participants were between 19 and 50 years old.

The patches for Treatments A and C were applied to a clean, dry,relatively hair free area of the upper arm. Treatments were applied toalternating arms. The NP101 patches for Treatments D and E were appliedto a clean, dry, relatively hair free area of the upper back. Treatmentswere applied to alternating right and left positions on the upper back.PK blood samples were scheduled for collection per subject for each ofthe five periods.

For Treatments A and B, 4 mL blood samples for sumatriptan plasmaconcentrations were collected by catheter or venipuncture into EDTAcollection tubes at the scheduled collection times. For Treatments C, Dand E, 2.7 mL blood samples for sumatriptan plasma concentrations werecollected by catheter or venipuncture into EDTA collection tubes at thescheduled collection times. Blood samples were cooled in an ice bath andcentrifuged as soon as possible after collection. Plasma samples werestored in labeled tubes at −20° C. Standard safety assessments were alsoperformed during each treatment period and at the conclusion of thestudy, including adverse event monitoring, clinical safety laboratorytests, and vital signs. Iontophoretic delivery system assessmentsincluding adhesion and dermal irritation and the amount of adhesiveresidue on the skin were performed during Treatments A, C, D and E.

The subjects were healthy adult volunteers (four males and five females)who were willing to attend the clinic for five treatment periods. Thesubjects received no other medication (prescription or over-the-counter)for two weeks prior to study entry, unless approved by the designatedphysician. Study participants were between 19 and 50 years old. The meanage was 28 years old.

The five treatments, as described in Table 1, were administered in fiveclinical periods. Four of the five dosing treatments were using thepatches comprising the formulations of the invention. The patch wasapplied to the upper arm or upper back depending on the Treatmentperiod.

In treatment B, the subjects received an Imigran FTab oral tablet (100mg sumatriptan succinate) with 240 mL of water after an overnight fast.Subjects remained fasted for 4 hours after dosing.

The drug reservoir pad (anode) formulation for Treatment A, C, D and Ewas: 10% polyamine formulation plus 4% sumatriptan succinate (loadedwith up to 120 mg of sumatriptan).

The salt reservoir pad (cathode) formulation for Treatments A, C, D andE was: 2% hydroxypropylcellulose (HPC) and NaCl.

There were no serious adverse events reported during the study periods.The most frequently reported adverse event was headache related toTreatment B (sumatriptan succinate 100 mg oral tablet) and tingling anditching at patch site for patch treatments A, C, D and E.

Mean skin erythema scores were also calculated for each of the patchtreatments. Immediately after patch removal, mean scores were 1.40 orbelow for each of the four patch treatments. After 72 hours, the meanscores were each below 1.00.

Nine subjects were dosed with patch Treatment A and Treatment B, the 100mg sumatriptan oral tablet. Seven subjects were treated with patchTreatments C, D, and E. Descriptive statistics for the PK parameters,AUC_(0-inf), AUC_(0-last), C_(max), T_(max), Lambda and t_(1/2), werecalculated. Arithmetic means of AUC_(0-inf) range from 99 to 144 ng/mLfor patches (Treatment A: 99 ng/mL; Treatment C: 99 ng/mL; Treatment D:144 ng/mL; and Treatment E: 105 ng/mL) and is about 225 ng/mL*h forTreatment B. Arithmetic means of half-life (T 1/2) range from 2.6 to 3hours for the patches (Treatment A: 3.0 hr; Treatment C: 2.7 hr;Treatment D: 2.6 hr; and Treatment E: 2.5 hr) and is about 3.4 hours forTreatment B.

The results of analysis of variance among the treatment groups inAUC_(0-inf), AUC_(0-last), and C_(max) were also analyzed. Treatment B(sumatriptan 100 mg oral tablet) is statistically different (p<0.001)from all patch treatments (A, C, D, and E) studied in all PK parameters.Treatment A and C are somewhat similar in their PK profile; both aredifferent from Treatment D in AUC_(0-inf), AUC_(0-last), and C_(max);both are not different from Treatment E in AUCs. Furthermore, bothTreatment A and Treatment C have lower C_(max) compared to Treatment E.

Example 2 Study of Patch Pharmacokinetics as Compared to Oral, Nasal andSubcutaneous Injections of Sumatriptan

In this example, the iontophoretic patches of the invention werecompared to the currently approved oral, subcutaneous (SQ) injection andnasal spray formulations of Imitrex® in healthy volunteers. Thebioavailability of the drug was compared to the bioavailability relativeto the 6 mg SQ injection.

This was a single center, open label, randomized, single-dose, crossoverstudy, wherein subjects were to receive seven study treatments insequence according to the randomization schedule, separated by a 3 to 10day washout period.

The drug being tested was sumatriptan succinate in the iontophoreticpatch of the invention. The patch was compared to three formulations ofImitrex® (100 mg oral sumatriptan succinate tablet (Treatment B), 6 mgsubcutaneous injection (Treatment C) and 20 mg intranasal spray(Treatment D)).

Subjects were admitted on Day-1, at least 12 hours prior to dosing onDay 1 of each treatment period, and remained in the clinical unit undersupervision until the last PK sample was obtained. During each treatmentperiod, blood was obtained at prescribed times for PK analysis.

Subjects

A total of 25 subjects (12 females and 13 males) were enrolled in thestudy and all received sumatriptan. Overall, 16 (64%) subjects completedthe study. As indicated in Table 2 four subjects withdrew consent; 3subjects discontinued the study due to an adverse event; 1 subject waslost to follow-up; and, 1 subject discontinued due to a protocolviolation. Study participants were between 21 and 57 years old.

All 25 enrolled subjects were treated with sumatriptan: 23 subjectsreceived control treatments (Treatments B (100 mg oral sumatriptansuccinate tablet), C (6 mg subcutaneous injection), and D (20 mgintranasal spray)) and 17 subjects had at least one patch of theinvention (Treatments A, E, F or G, as shown in Table 2).

TABLE 2 Wear Time mA Cathode Treatment Worn (hr) Waveform Min AnodeReservoir Reservoir A, F Upper 4 4 mA 1.0 hr 600 3.0 g of sumatriptangel 3.0 g of 2% arm then 2.0 mA solution (10% polyamine Hydroxypropylfor 3.0 hrs and 4% sumatriptan cellulose (HPC) succinate) containing 120mg and NaCl of sumatriptan succinate E, G Upper 4 4 mA 1.0 hr 600 2.6 gof sumatriptan gel 2.6 g of 2% arm then 2.0 mA solution (10% polyamineHydroxypropyl for 3.0 hrs and 4% sumatriptan cellulose (HPC) succinate)containing 104 mg and NaCl of sumatriptan succinatePhamacokinetic Analysis

Serial blood samples for PK analysis were collected by catheter orvenipuncture into EDTA collection tubes at predetermined times accordingto treatment for the determination of sumatriptan concentrations inplasma. The plasma samples were analyzed by a validated HPLC with MS/MSdetection.

The following PK parameters were determined: C_(max), T_(max), λ_(z),t_(1/2), AUC_(0-last), AUC_(0-inf) and total body clearance (Cl/F). Thebioavailability (F) of the non-parenteral formulations were assessedrelative to the SQ injection.

PK parameters for sumatriptan were calculated from the actual plasmaconcentration-time data using non-compartmental method with WinNonlin™computer program. PK parameters for each treatment were reported alongwith descriptive statistics.

Analysis of variance (ANOVA) was used to compare AUC_(0-inf) and C_(max)values between treatments. AUC_(0-last), T_(max) and t_(1/2) weresummarized descriptively.

The mean clearance for the 17 subjects who had Treatments F and G was54483 mL/hr. Table 3 below provides a summary of arithmetic means of thepharmacokinetic parameters for each treatment group.

TABLE 3 AUC_(0-inf) AUC_(0-last) C_(max) T_(max) t_(1/2) ² Lambda_zTreatment Group¹ (hr * ng/mL) (hr * ng/mL) (ng/mL) (hr) (hr) (/hr) SQ (n= 23) 113.60 111.42 82.24 0.25 2.21 0.31 Nasal (n = 23) 50.25 48.7212.49 1.45 2.24 0.31 Oral (n = 23) 247.14 237.40 51.61 2.24 4.82 0.16Treatment F (n = 17) 113.45 111.51 24.76 1.65 2.94 0.22 Treatment G (n =17) 112.92 111.01 23.05 2.53 2.86 0.23 ¹Treatment groups: B = Oral, C =SQ, D = Nasal, F = Patch Treatment F, and G = Patch Treatment G ²t_(1/2)= 0.693/Lambda_z

Pharmacokinetic parameters, including AUC_(0-inf), AUC_(0-last),C_(max), Lambda_z, t_(1/2), and T_(max), for the two patches of theinvention and the three positive controls (Treatments B, C, and D) areoutlined in Table 4 (Arithmetic Means). The parameters derived directlyfrom the plasma concentration data are presented as “observedparameters”; AUC and C_(max) derived directly from the plasmaconcentration data.

TABLE 4 Pharmacokinetic Parameters by Treatment Group Arithmetic Mean(95% CI) CV Parameter Group¹ n Mean Lower Upper Min Max Median (%) SDAUC_(0-inf) SQ 23 113.60 106.57 120.64 79.40 135.44 113.81 14.3 16.261(hr * ng/mL) Nasal 23 50.25 40.80 59.71 5.27 99.21 51.03 43.5 21.873Oral 23 247.14 215.19 279.09 155.66 457.51 230.44 29.9 73.890 Patch F 17113.45 99.04 127.86 67.10 157.57 106.83 24.7 28.028 Patch G 17 112.92102.49 123.34 76.70 146.58 117.13 18.0 20.276 AUC_(0-last) SQ 23 111.42104.37 118.46 77.71 134.57 112.19 14.6 16.292 (hr * ng/mL) Nasal 2348.72 39.35 58.08 4.67 97.97 49.96 44.4 21.652 Oral 23 237.40 205.71269.08 148.74 451.62 221.61 30.9 73.265 Patch F 17 111.51 97.29 125.7465.79 155.76 105.50 24.8 27.665 Patch G 17 111.01 100.70 121.31 74.77143.39 115.73 18.1 20.045 C_(max) SQ 23 82.24 75.59 88.89 52.10 108.083.10 18.7 15.369 (ng/mL) Nasal 23 12.49 10.12 14.85 2.25 26.10 11.3043.8 5.468 Oral 23 51.61 43.15 60.07 22.40 108.0 47.50 37.9 19.567 PatchF 17 24.76 21.4 28.115 13.6 38 24.1 26.368 6.528 Patch G 17 23.05 20.4925.609 14.3 33.3 23.8 21.618 4.982 T_(max) SQ 23 0.25 0.21 0.28 0.170.33 0.17 33.1 0.082 (hr.) Nasal 23 1.45 1.08 1.82 0.17 4.00 1.50 58.30.846 Oral 23 2.24 1.79 2.69 0.50 4.00 2.00 46.1 1.032 Patch F 17 1.651.02 2.28 1.00 4.00 1.00 74.2 1.222 Patch G 17 2.53 1.80 3.26 1.00 4.003.00 56.1 1.419 t_(1/2) ⁴ SQ 23 2.21 1.94 2.47 1.35 4.12 2.09 27.7 0.611(hr.) Nasal 23 2.24 1.89 2.60 1.30 4.79 2.04 36.7 0.823 Oral 23 4.823.41 6.23 2.58 17.57 3.74 67.6 3.259 Patch F 17 2.94 2.70 3.19 1.70 3.592.91 16.2 0.475 Patch G 17 2.86 2.60 3.11 1.96 3.79 2.84 17.5 0.499Lambda_z SQ 23 0.31 0.28 0.34 0.16 0.47 0.31 24.2 0.075 (/hr.) Nasal 230.31 0.28 0.35 0.13 0.49 0.31 27.9 0.087 Oral 23 0.16 0.14 0.18 0.040.25 0.17 31.7 0.051 Patch F 17 0.22 0.20 0.25 0.18 0.38 0.22 20.6 0.046Patch G 17 0.23 0.21 0.25 0.17 0.33 0.22 18.5 0.043

AUC_(0-inf) arithmetic means for the 6 mg SQ injection, 100 mg oralpreparation, and 20 mg nasal preparation were 114 hr*ng/mL, 247hr*ng/mL, and 50 hr*ng/mL, respectively. Both treatments F and G yieldedAUC_(0-inf) of approximately 113 hr*ng/mL.

Arithmetic means of C_(max) for oral, nasal, and injection groups were51.6 ng/mL, 12.5 ng/mL, and 82.2 ng/mL, respectively. Arithmetic meansof C_(max) for the patches ranged from 24.7 ng/mL (Treatment F) to 23.1ng/mL (Treatment G). T_(max) was 0.25 hour for the injection, 1.45 hourfor nasal, and 2.24 hour for the oral formulation. Apparent T_(max) forTreatment F was 1.65 hour and Treatment G was 2.53 hour.

The elimination half-life was 2.21 hours for injection, 2.24 hours fornasal, and 4.84 hours for oral. The elimination half-life after removingthe patch was 2.94 hours for Treatment F and 2.86 hours for Treatment G.The terminal half-life for the oral formulation in this study may haveappeared greater than previously reported^(10,11) because of the highsensitivity of PPD LCMS method used (limit of quantification equal 0.200ng/mL), resulting in quantification of clinically insignificant levels,possibly reflecting the presence of a deep compartment.

Safety Evaluation:

There were no deaths or serious adverse events reported in this study.

There were no unexpected adverse events or a significant increase in thefrequency of commonly reported adverse events in subjects receiving thepatch of the invention compared with oral, nasal and subcutaneousadministration of sumatriptan.

Atypical sensations, and pain and pressure sensations, which arecommonly reported for oral and subcutaneous sumatriptan (as shown inTable 5), were not reported following the patch Treatments F and Gpatch. This may reflect in part the lower C_(max) levels obtained withthe patch treatments.

Adverse events were also categorized into two special groupings; (1)Atypical Sensations and (2) Pain and Pressure Sensations. This was doneto be consistent with current triptan labeling which sought to captureboth various short-lived side effects associated with triptans (i.e.sensation of warmth / cold, paresthesias) and which are grouped as‘Atypical Sensations’, and “Pain and Pressure Sensations”. The majorityof these adverse events, Atypical Sensations and Pain and PressureSensations (Table 5), occurred in close proximity to the T_(max) insubjects treated with oral and subcutaneous sumatriptan.

TABLE 5 Atypical Sensations/Pain and Pressure Sensations n (%) SubjectsReported Event Treatment C Treatment B Treatment D Treatment F TreatmentG Adverse Event SubQ Oral Nasal Patch F Patch G Grouping Preferred Term(N = 23) (N = 23) (N = 23) (N = 17) (N = 17) Atypical Any AEs 14 (60.9%)2 (8.7%) — — — Sensation Burning sensation mucosal  3 (13.0%) — — — —Ear discomfort 1 (4.3%) — — — — Facial pain 1 (4.3%) — — — — Feeling hot2 (8.7%) — — — — Flushing  6 (26.1%) — — — — Head discomfort 1 (4.3%) 1(4.3%) — — — Hot flush  3 (13.0%) 1 (4.3%) — — — Paraesthesia — — —Sensation of heaviness 1 (4.3%) — — — Sensation of pressure 1 (4.3%) — —— Pain and Any AEs 2 (8.7%)  4 (17.4%) — — — Pressure Sensation Neckpain 2 (8.7%) — — — Sensation of heaviness 1 (4.3%) 1 (4.3%) — — —Sensation of pressure 1 (4.3%) 1 (4.3%) — — —

Adverse events associated with the patch of the invention were ingeneral mild and most resolved without treatment.

Regarding treatments with the iontophoretic patch of the inventionoverall, no subject in this study had a skin irritation score of 3 or 4at any time. There were no subject discontinuations directlyattributable to patch treatments (application site disorders). Skinirritation scores were either scored 0 or 1 by 72 hours. Skin irritationscores were statistically better (i.e., lower mean score) for TreatmentF compared to Treatment G at 48 and 72 hours post patch removal. At 72hours or at 10 day follow-up, all skin irritation scores were “0” (noerythema).

At the time of patch removal, more than 75% of the subjects had minimalor no erythema. By 48 hours post patch removal all subjects had minimalor no erythema (NB: one assessment was not done for Treatment F). At 72hours all of the subjects treated with Treatment F had no erythema (NB:one assessment was not done for Treatment F). For subjects that hadminimal erythema at 72 hours (35.3% of Treatment G subjects) theerythema completely resolved by the day 10 follow-up. In general, thesefindings (Table 6) were not clinically different from those observed insubjects treated with Patches A and E.

TABLE 6 Skin Irritation Mean Score - Directly Under the Drug PadSubjects Treated with Patches F and G Area Time Point Statistics Patch FPatch G Skin Directly Patch Removal Sample Size 17 17 Under the Drug PadMean 1.1 1.1 Standard Deviations 0.49 0.66 Minimum 0.0 0.0 Maximum 2.02.0 Median 1.0 1.0 24 hours Sample Size 17 17 Mean 0.9 0.7 StandardDeviations 0.66 0.69 Minimum 0.0 0.0 Maximum 2.0 2.0 Median 1.0 1.0 48hours Sample Size 16 17 Mean 0.2 0.6 Standard Deviations 0.40 0.51Minimum 0.0 0.0 Maximum 1.0 1.0 Median 0.0 1.0 72 hours Sample Size 1617 Mean 0.0 0.4 Standard Deviations 0.00 0.49 Minimum 0.0 0.0 Maximum0.0 1.0 Median 0.0 0.0

Overall, the safety profile seen in this study reflects the known safetyprofile of oral, subcutaneous and nasally administered sumatriptan.Sumatriptan administration via the patch did not reveal any unexpectedadverse events and was well tolerated.

Results

The pharmacokinetic results for Treatments B, C, and D (thesubcutaneous, oral and nasal methods of administering) were comparableto those presented in the approved product labels. The sumatriptanplasma concentration time curves for both the iontophoretic patches ofthe invention were not substantially different from each other, 10indicating that transdermal delivery of sumatriptan is not significantlyinfluenced by differences in formulation loading in the 2.6-3.0 gramrange. Treatments using the patches of the invention yieldedpharmacokinetics of plasma sumatriptan intermediate between Treatment D(20 mg sumatriptan nasal spray) and Treatment B (100 mg sumatriptan oraltablets). The patches of the invention delivered sumatriptan withC_(max) of 23-25 ng/mL and sustained plasma concentrations ofsumatriptan in this range for the full 4 hours of current flow. Theseresults confirm and extend pharmacokinetic data obtained in Example 1.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by thefollowing claims. The contents of all references, patents, and patentapplications cited throughout this application are hereby incorporatedby reference. The appropriate components, processes, and methods ofthose patents, applications and other documents may be selected for thepresent invention and embodiments thereof.

The invention claimed is:
 1. A method for treating a sumatriptanresponsive state in a human, comprising iontophoretically administeringto said human an effective amount of sumatriptan using a current ofabout 4 mA for a high current treatment period of about one hour and acurrent of about 2 mA for a subsequent low current treatment period,such that said human is treated for said sumatriptan responsive state,wherein the sumatriptan is administered such that an AUC_(0-inf) ofbetween about 67 and about 158 hr*ng/mL within a 95% confidence intervalis achieved in the human's plasma; and wherein the sumatriptan isadministered such that a C_(max) of between about 14 and about 38 ng/mLwithin a 95% confidence interval is achieved in the human's plasma. 2.The method of claim 1, wherein said amount of sumatriptan is about 10mg.
 3. The method according to claim 1, wherein the sumatriptan isadministered such that an AUC_(0-inf) between about 99 and 128 hr*ng/mLwithin a 95% confidence interval is achieved in the human's plasma and aC_(max) between about 20 and about 28 ng/mL within a 95% confidenceinterval is achieved in the human's plasma.
 4. The method of claim 3,wherein about 10 mg of sumatriptan is administered to said human.
 5. Themethod according to claim 1, wherein the sumatriptan is administeredsuch that an AUC_(0-inf) between about 99 and about 128 hr*ng/mL withina 95% confidence interval is achieved in the human's plasma; or whereinthe sumatriptan is administered such that a C_(max) between about 20 andabout 28 ng/mL within a 95% confidence interval is achieved in thehuman's plasma; or wherein the sumatriptan is administered such that aC_(max) of about 23-25 ng/mL is achieved and plasma concentrations aresustained for at least three hours; or wherein the sumatriptan isadministered such that an AUC_(0-inf) between about 99 and 128 hr*ng/mLand a C_(max) between about 20 to about 28 ng/mL are achieved in thehuman's plasma.
 6. The method according to claim 1, wherein saideffective amount of sumatriptan is administered without substantialadverse effects.
 7. The method of claim 6, wherein said adverse effectscomprise pain, pressure sensations or atypical sensations.
 8. The methodaccording to claim 1, wherein said administration of sumatriptan resultsin an AUC_(0-inf), t_(1/2), or C_(max) coefficient of variance (CV) ofless than about 25%.
 9. The method according to claim 1, wherein saidadministration of sumatriptan results in an AUC_(0-inf) coefficient ofvariance less than twice the AUC_(0-inf) coefficient of variance forsubcutaneous administration of sumatriptan.
 10. The method of claim 1,wherein said effective amount of sumatriptan is administered withoutsubstantially irritating said human's skin.
 11. The method of claim 10,wherein said iontophoretic administration of sumatriptan causes littleor no erythema.
 12. The method of claim 10, wherein said iontophoreticadministration of sumatriptan causes little or no punctuate lesions. 13.The method of claim 1, wherein said sumatriptan responsive state is amigraine.
 14. A method for treating a sumatriptan responsive state in ahuman, comprising iontophoretically administering to said human anamount of sumatriptan using a current of 4.0 mA or greater for at leasta portion of the treatment period, such that said sumatriptan responsivestate in said human is treated, wherein the sumatriptan is administeredsuch that an AUC_(0-inf) of between about 67 and about 158 hr*ng/mLwithin a 95% confidence interval is achieved in the human's plasma; andwherein the sumatriptan is administered such that a C_(max) of betweenabout 14 and about 38 ng/mL within a 95% confidence interval is achievedin the human's plasma.
 15. The method of claim 14, wherein said portionof said treatment period is about thirty minutes to about 90 minutes.16. The method of claim 14, wherein said method further comprises a lowcurrent treatment period using a current of between about 1.5 to about2.5 mA.
 17. The method of claim 16, wherein said low current treatmentperiod uses a current of about 2.0 mA.
 18. The method of claim 16,wherein said low current treatment period is between about 2 hours andabout 4 hours in length.
 19. The method of claim 14, wherein aneffective amount of sumatriptan is administered without substantiallyirritating said human's skin.
 20. The method of claim 19, wherein saidiontophoretic administration of sumatriptan causes little or noerythema.
 21. The method of claim 19, wherein said iontophoreticadministration of sumatriptan causes little or no punctuate lesions. 22.The method of claim 14, wherein said sumatriptan responsive state is amigraine.